Corneal Collagen Cross-Linking

The Medicare Advantage Medical Policies are designed to provide guidance regarding the decision-making process for the coverage or non-coverage of services or procedures in accordance with the member EOC and the Centers of Medicare and Medicaid Services (CMS) policies, when available. In the event of a conflict, applicable CMS policy or EOC language will take precedence over the Medicare Advantage Medical Policy. In the absence of CMS guidance for a requested service or procedure, the health plan may apply their Medical Policy Manual or MCGTM criteria, both of which are developed with an objective, evidence-based process using scientific evidence, current generally accepted standards of medical practice, and authoritative clinical practice guidelines.


Policy Guidelines
Progressive keratoconus is defined as one or more of the following: • An increase of 1 diopter (D) in the steepest keratometry value • An increase of 1 D in regular astigmatism evaluated by subjective manifest refraction • A myopic shift (decrease in the spherical equivalent) of 0.50 D on subjective manifest refraction • A decrease ≥0.1 mm in the back optical zone radius in rigid contact lens wearers where other information was not available.

Treatment of Keratoconus and Ectasia
The initial treatment for keratoconus often consists of hard contact lenses. A variety of keratorefractive procedures have also been attempted, broadly divided into subtractive and additive techniques. Subtractive techniques include photorefractive keratectomy or laser in situ keratomileuses, although generally, results of these techniques have been poor. Implantation of intrastromal corneal ring segments (see medical policy 00164) is an additive technique in which the implants are intended to reinforce the cornea, prevent further deterioration, and potentially obviate the need for penetrating keratoplasty. Penetrating keratoplasty (ie, corneal grafting) is the last line of treatment. About 20% of patients with keratoconus will require corneal transplantation. All of these treatments attempt to improve the refractive errors but are not disease-modifying.
Treatment options for ectasia include intraocular pressure-lowering drugs and intracorneal ring segments. Frequently, penetrating keratoplasty is required.
None of the currently available treatment options for keratoconus and corneal ectasia halt the progression of the disease, and corneal transplantation is the only option available when functional vision can no longer be achieved.
Corneal collagen cross-linking has the potential to slow the progression of the disease. It is performed with the photosensitizer riboflavin (vitamin B2) and ultraviolet A irradiation. There are 2 protocols for corneal collagen cross-linking: 1. Epithelium-off corneal collagen cross-linking (also known as "epi-off"): In this method, about 8 mm of the central corneal epithelium is removed under topical anesthesia to allow better diffusion of the photosensitizer riboflavin into the stroma. Following deepithelialization, a solution with riboflavin is applied to the cornea (every 1-3 minutes for 30 minutes) until the stroma is completely penetrated. The cornea is then irradiated for 30 minutes with ultraviolet A 370 nm, a maximal wavelength for absorption by riboflavin, while the riboflavin continues to be applied. The interaction of riboflavin and ultraviolet A causes the formation of reactive oxygen species, leading to additional covalent bonds (crosslinking) between collagen molecules, resulting in stiffening of the cornea. Theoretically, by using a homogeneous light source and absorption by riboflavin, the structures beyond a 400mm thick stroma (endothelium, anterior chamber, iris, lens, retina) are not exposed to an ultraviolet dose that is above the cytotoxic threshold. 2. Epithelium-on corneal collagen cross-linking (also known as "epi-on" or transepithelial): In this method, the corneal epithelial surface is left intact (or may be partially disrupted) and a longer riboflavin loading time is needed.
Currently, the only corneal collagen cross-linking treatment approved by the U.S. Food and Drug Administration (FDA) is the epithelium-off method. There are no FDA approved corneal collagen cross-linking treatments using the epithelium-on method. Corneal collagen cross-linking is being evaluated primarily for corneal stabilization in patients with progressive corneal thinning, such as keratoconus and corneal ectasia following refractive surgery. Corneal collagen cross-linking may also have anti-edematous and antimicrobial properties.

U.S. Food and Drug Administration (FDA)
In 2016, riboflavin 5-phosphate in 20% dextran ophthalmic solution (Photrexa Viscous ® ‡ ; Avedro) and riboflavin 5-phosphate ophthalmic solution (Photrexa ® ‡ ; Avedro) were approved by the FDA for use with KXL System in corneal corneal collagen cross-linking for the treatment of progressive keratoconus and corneal ectasia after refractive surgery.

Rationale/Source
Corneal collagen cross-linking is a photochemical procedure approved by the U.S. Food and Drug Administration (FDA) for the treatment of progressive keratoconus and corneal ectasia. Keratoconus is a dystrophy of the cornea characterized by progressive deformation (steepening) of the cornea No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.

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while corneal ectasia is keratoconus that occurs after refractive surgery. Both lead to functional loss of vision and need for corneal transplantation.
For individuals who have progressive keratoconus who receive corneal collagen cross-linking using riboflavin and ultraviolet A, the evidence includes multiple randomized controlled trials (RCTs), systematic reviews, and nonrandomized studies. Relevant outcomes are change in disease status, functional outcomes, and treatment-related morbidity. In both pivotal RCTs, the primary endpoint (an intermediate outcome) of reducing maximum corneal curvature by 1 diopter (D) was achieved at month 3 and maintained at months 6 and 12 in corneal collagen cross-linking treated patients compared with sham controls. In both RCTs, the difference in mean change in maximum corneal curvature from baseline to 12 months was 1.9 D and 2.3 D, respectively, favoring the corneal collagen cross-linking treated patients. Several other studies measured visual acuity and found significant and lasting improvements in corrected visual acuity and other measures with corneal collagen cross-linking. Long-term follow-up for visual acuity outcomes is needed. The adverse events associated with corneal collagen cross-linking include corneal opacity (haze), corneal epithelial defects, and other ocular findings. Most adverse events resolved in the first month but continued in a few (1%-6%) patients for 6 to 12 months. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have corneal ectasia after refractive surgery who receive corneal collagen crosslinking using riboflavin and ultraviolet A, the evidence includes multiple RCTs and nonrandomized studies. Relevant outcomes are change in disease status, functional outcomes, and treatment-related morbidity. In both pivotal RCTs, the primary endpoint (an intermediate outcome) of reducing maximum corneal curvature by 1 D was achieved at month 3 and maintained at months 6 and 12 in the corneal collagen cross-linking treated patients compared with sham controls. In both RCTs, the difference in mean change in maximum corneal curvature from baseline to 12 months was 2.0 D and 1.1 D, respectively, favoring corneal collagen cross-linking treated patients. Other trials showed significant improvements not only in maximum corneal curvature but also visual acuity measures in the corneal collagen cross-linking groups compared with the control groups. The first and longest trial followed patients up to 3 years and saw continued improvement in visual acuity with corneal collagen cross-linking. Long-term follow-up for visual acuity outcomes is needed. The adverse events associated with corneal collagen cross-linking were the same for the ectasia trials as for the keratoconus. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.

Supplemental Information Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
In response to requests, input was received from 1 physician specialty society and 1 academic medical center (2 reviewers) while this policy was under review in 2012. The input was mixed, noting the limited literature and lack of U.S. Food and Drug Administration (FDA) approval for this procedure, although there are ongoing clinical trials regulated by the FDA. Reviewers also commented on the lack of alternatives to slow disease progression, and that data indicated the procedure is safe and effective enough to offer to patients with adequate informed consent under an investigational protocol.

Practice Guidelines and Position Statements National Institute for Health and Care Excellence
In 2013, the National Institute for Health and Care Excellence (NICE) issued guidance on corneal collagen cross-linking using riboflavin and ultraviolet A, updating its 2009 guidance. The 2013 guidance stratified recommendations for corneal collagen cross-linking as follows: "Most of the published evidence on photochemical corneal collagen cross-linkage using riboflavin and ultraviolet A (UVA) for keratoconus and keratectasia relates to the technique known as 'epithelium-off corneal collagen cross-linking'. 'Epithelium-on (transepithelial) corneal collagen cross-linking' is a more recent technique and less evidence is available on its safety and efficacy. Either procedure (epithelium-off or epithelium-on corneal collagen crosslinking) can be combined with other interventions, and the evidence base for these combination procedures (known as 'corneal collagen cross-linking plus') is also limited. Therefore, different recommendations apply to the variants of this procedure, as follows.
1.1 Current evidence on the safety and efficacy of epithelium-off corneal collagen cross-linking for keratoconus and keratectasia is adequate in quality and quantity. Therefore, this procedure can be used provided that normal arrangements are in place for clinical governance, consent and audit. 1.2 Current evidence on the safety and efficacy of epithelium-on (transepithelial) corneal collagen cross-linking, and the combination (corneal collagen cross-linking plus) procedures for keratoconus and keratectasia is inadequate in quantity and quality. Therefore, these procedures should only be used with special arrangements for clinical governance, consent and audit or research."

U.S. Preventive Services Task Force Recommendations
Not applicable.

Medicare National Coverage
There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table  1. CPT is a registered trademark of the American Medical Association.
Codes used to identify services associated with this policy may include (but may not be limited to) the following: Code Type Code CPT 0402T, 66999 HCPCS J2787 ICD-10 Diagnosis H18.601-H18.609, H18.711-H18.719 *Investigational -A medical treatment, procedure, drug, device, or biological product is Investigational if the effectiveness has not been clearly tested and it has not been incorporated into